Chronic Fatigue Syndrome (CFS) patients have registered cognitive complaints such as impaired concentration, memory lapses, and confusion. These complaints are cited as the most debilitating aspect of their disorder. Our pilot study, funded through the New Jersey Chronic Fatigue Research Center, showed that acquisition of a new motor response is impaired in CFS patients. Failure to acquire the classically conditioned eyeblink response was associated with white matter abnormalities in the prefrontal cortex, which are more prevalent in CFS patients without a concurrent psychiatric diagnosis. The present proposal seeks to determine the nature and diagnostic specificity of the learning deficit, as well as advance our understanding of the pathophysiology of some of the cognitive complaints in CFS. We will compare acquisition of the classically conditioned eyeblink response in CFS patients without a concurrent diagnosis of depression to CFS patients with concurrent depression, depressed patients, and healthy sedentary controls. A two-tone discrimination procedure, wherein one tone (CS+) predicts the onset of the unconditioned stimulus (US) and one which does not (CS-), will be used. In this study, we will address two hypotheses derived from neuropsychological research, namely, that CFS patients without depression have slower information processing and they are also impaired in their ability to processes complex auditory information. To address the former, we will manipulate the time between CS+ onset and US onset, the interstimulus interval. To address the latter, we will reverse the contingencies between the CS+ and CS- with respect to the US. Learning of the eyeblink response will be related to performance on neuropsychological tests. We will also obtain MRI scans to quantify brain abnormalities. In this manner, we will relate the prevalence of brain abnormalities in CFS patients to learning and memory impairments. In the absence of a medical marker of the disorder, the diagnosis of CFS relies on concordance with the current case definition. The lack of a medical marker also hinders efforts toward an identification of the pathophysiology of CFS. Our strategy will be to employ a learning and memory paradigm about which a great deal is known concerning the underlying neuroanatomy, neurophysiology and neuropharmacology. We will then be in a position to relate learning abnormalities to brain pathology as measured in MRI scans and characterized by neuropsychological deficits.